We recently described novel serological assays that revealed for the first time a complex and lengthy maturation of envelope-specific antibody responses to HIV-1 and animal lentivirus (SIV, SHIV, EIAV, FIV) infections, Using these novel serological parameters to characterize antibody responses elicited by a diverse panel of experiments SIV)and EIAV) vaccines , we further demonstrated a close association between protective efficacy and the extent of immune maturation achieved by a particular vaccine. Based on this model of immature/non-protective and mature/protective antibody responses, we hypothesize that a more detailed definition of the maturation of envelope-specific antibody responses to experimental SIV and SHIV vaccines can provide fundamental new insights into the nature of protective immunity and provide new parameters that can be used as predictive immune correlates of experimental vaccine SIV and HIV-1 envelope proteins, i.e., "domain- specific serology", can provide a higher resolution definition of the antibody responses to vaccines compared to the use of complete envelope protein antigens in serological assays. Therefore, we propose the following specific aims to develop and evaluate domain-specific serology in the SIV and SHIV monkey vaccine models: (1) To map and characterize conformationally dependent epitopes of SIV envelope proteins using complementary techniques of HIV-1/ SIV chimeric antigens and antibody protected proteolysis. (2) To develop deep novel domain-specific serological assays to characterize the maturation of antibody responses to attenuated SIV vaccines and its association with the development of protective immunity, (3) To evaluate domain-specific serology as a correlate of SIV vaccine efficacy in experimental trials of subunit, DNA, live attenuated and vector expression-based vaccine trials. (4) To develop domain-specific serological assays to map HIV-1 envelope antigenic determinants, to characterize the maturation of antibody responses to SHIV infection, and to identify immune correlates of SHIV vaccine efficacy. It is anticipated that the information gained from the proposed domain- specific serological studies in the SIV and SHIV vaccine models will provide importance guidance for the design of human AIDS vaccine strategies and validate the new serological methods as potential correlates of HIV-1 vaccine efficacy in human clinical trials.